The prefrontal cortex in primates receives signals from the entire neuraxis and uses them selectively to focus on the task at hand. This process is guided by attention mechanisms that engage prefrontal and anterior cingulate cortices to select relevant signals and suppress distracters. The balance in excitatory-inhibitory control is disrupted in several neuropsychiatric diseases that affect these areas. The subgenual cingulate area 25 shows abnormally heightened activity in humans with major depressive disorder but the circuit mechanisms are elusive. The goal of the proposed study is to investigate the largely unexplored circuitry of area 25 in a normal primate animal model. The working hypothesis is that specific cellular features of area 25 and distinct interactions with excitatory and inhibitory neurons and receptors in other frontal, temporal and thalamic structures underlie the normal plasticity of area 25 as well as its increased vulnerability to functional disruption. Experiments are designed to test this hypothesis at high resolution in normal rhesus monkeys through study of: (1) Glial and axon features in area 25 associated with neural remodeling, conduction, and synaptic function; and the connections of area 25 with other cortices. (2) Serial pathways through which lateral prefrontal cortex may modulate activity in area 25 through the anterior cingulate area 32, by innervating excitatory and functionally distinct classes of inhibitory neurons. (3) The relationship of pathways that link anterior cingulate areas to serotonin and glutamate receptors which affect activity in area 25. (4) Study of key circuits which link the hippocampus with area 25, and link both structures with the inhibitory thalamic reticular nucleus, in a network associated with attention and the contextual significance of stimuli. (5) Computational modeling to investigate how processing through the extended area 25 network affects attention and appreciation of context and is disrupted in depression. Hypotheses about pathway interactions are based on a theoretical framework that helps predict laminar patterns of connections based on laminar structure. Multiple neural pathways will be labeled with tracers, combined with double- or triple-labeling of distinct classes of inhibitory neurons and receptors. Brain tissue will be processed to view at the light, confocal, and electron microscopic level to conduct quantitative analyses from the system of pathways to their synapses. Findings from these studies will provide the foundation to unravel the role of prefrontal pathways in excitatory-inhibitory control. The neural features and pathways under study are affected in major depressive disorder and are targets for the development of novel antidepressants.